Tumor suppressive role for kinases phosphorylating p53 in <scp>DNA</scp> damage‐induced apoptosis

Yogosawa, Satomi; Yoshida, Kiyotsugu

doi:10.1111/cas.13792

Cited by 124 publications

(85 citation statements)

References 74 publications

(164 reference statements)

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“…Although DYRK2 distinct role in cancer development has been broadly proved, there is controversy concerning its pro-or anti-tumour potentials. However, various studies have shown that DYRK2 is down-regulated in various cancer tissues such as lung, breast, prostate and colon, associated with poor patient prognosis [32,50,[65][66][67][68][69]. The data showing the correlation in the levels of both proteins in tumour tissue (Fig.…”

Section: Discussionmentioning

confidence: 92%

Phosphorylation-dependent regulation of the NOTCH1 intracellular domain by dual-specificity tyrosine-regulated kinase 2

Morrugares

Correa-Sáez

Moreno

et al. 2019

Cell. Mol. Life Sci.

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NOTCH proteins constitute a receptor family with a widely conserved role in cell cycle, growing and development regulation. NOTCH1, the best characterised member of this family, regulates the expression of key genes in cell growth and angiogenesis, playing an essential role in cancer development. These observations provide a relevant rationale to propose the inhibition of the intracellular domain of NOTCH1 (Notch1-IC) as a strategy for treating various types of cancer. Notch1-IC stability is mainly controlled by post-translational modifications. FBXW7 ubiquitin E3 ligase-mediated degradation is considered one of the most relevant, being the previous phosphorylation at Thr-2512 residue required. In the present study, we describe for the first time a new regulation mechanism of the NOTCH1 signalling pathway mediated by DYRK2. We demonstrate that DYRK2 phosphorylates Notch1-IC in response to chemotherapeutic agents and facilitates its proteasomal degradation by FBXW7 ubiquitin ligase through a Thr-2512 phosphorylation-dependent mechanism. We show that DYRK2 regulation by chemotherapeutic agents has a relevant effect on the viability, motility and invasion capacity of cancer cells expressing NOTCH1. In summary, we reveal a novel mechanism of regulation for NOTCH1 which might help us to better understand its role in cancer biology.

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Section: Discussionmentioning

confidence: 92%

Phosphorylation-dependent regulation of the NOTCH1 intracellular domain by dual-specificity tyrosine-regulated kinase 2

Morrugares

Correa-Sáez

Moreno

et al. 2019

Cell. Mol. Life Sci.

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“…Particularly, phosphorylation of p53 protein plays a critical role in modulating its activation to induce apoptosis in cancer cells. 8 TP53 activity decreases or disappears in cancer cells. The TP53 gene contains mutations in~50-60% of human cancers.…”

Section: Introductionmentioning

confidence: 98%

“…While it is almost undetectable in cells with normal protein levels, its expression increases in the presence of stress. The cells without stress are inactive . Thanks to the response it creates after cellular stress, TP53 affects functions of genes stopping cell cycle, leading to apoptosis, responsible for DNA repair and associated with aging and cellular metabolism .…”

Section: Introductionmentioning

confidence: 99%

“…Post‐translational modifications of p53 protein including phosphorylation, ubiquitination and acetylation at multiple sites are important to regulate its activation and subsequent transcriptional gene expression. Particularly, phosphorylation of p53 protein plays a critical role in modulating its activation to induce apoptosis in cancer cells . TP53 activity decreases or disappears in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

“…The cells without stress are inactive. 8 Thanks to the response it creates after cellular stress, TP53 affects functions of genes stopping cell cycle, leading to apoptosis, responsible for DNA repair and associated with aging and cellular metabolism. 9 TP53 induces apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of TP53 gene in uterine myomas: No mutations but P72R polymorphism is associated with myoma development

Altınkaya

Avcıoğlu

Sezer

et al. 2019

J of Obstet and Gynaecol

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Aim The aim of the present study was to investigate the familial and somatic mutations as well as polymorphisms of TP53 gene in patients with uterine leiomyoma. Methods The study included 35 women with histologically diagnosed as uterine leiomyomas at the Gynecology Department of Adnan Menderes University Faculty of Medicine. Tissue and blood samples were analyzed for mutations and polymorphisms of TP53 gene by next generation sequencing (Miseq—Illumina). Acquired data was compared with the normal data in Ensembl database. Data from 1000 genome project and data from exome sequencing analyses in Intergen Genetic Diagnosis Center (Ankara) were used as controls for polymorphism analyses. Results There were no mutations in tissue and blood samples. However, when the polymorphisms were evaluated, a significant difference was found in NM_000546.5(TP53):c.215C > G (p.Pro72Arg) polymorphism between the study and control groups. The results indicated that P72R/P72R genotype increased the risk of leiomyoma development by 6.3 fold (95% confidence interval [CI]: 2.880–13.793). There was a negative correlation between P72R/WT genotype and leiomyoma development (OR = 0.261, 95% CI: 0.114–0.596). P72R/P72R genotype was statistically higher in the patients with leiomyoma compared with the controls and 1000 genomes from Asian, European and World populations. Conclusion The results of the present study suggested that P72R/P72R genotype may be associated with development of uterine leiomyoma in the Turkish population in the Western part of the country.

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The long noncoding RNA NR_045363 involves cardiomyocyte apoptosis and cardiac repair via p53 signal pathway

Chen

Wang

Nie

et al. 2020

Cell Biology International

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Long noncoding RNAs (lncRNAs) can participate in various biological behaviors, including regulating cell differentiation, proliferation, and apoptosis. The investigators have previously confirmed that highly conserved lncRNA NR_045363 controls cardiomyocyte (CM) proliferation and cardiac repair. The present study investigates the effects of NR_045363 on CM apoptosis. Seven‐day‐old mice were subjected to permanent left anterior descending coronary artery ligation (LAD), and the NR_045363 expression was analyzed by quantitative real‐time polymerase chain reaction (qRT‐PCR). The expression of NR_045363 in the MI group significantly exceeded the Sham group during the first week after the operation. The NR_045363 expression was knocked down in primary cultured CMs using an NR_045363‐targeting lncRNA Smart silencer, and the apoptosis of CMs was analyzed by terminal‐deoxynucleoitidyl transferase mediated nick end labeling and Annexin‐V/PI double staining. These present results indicate that the NR_045363 knockdown significantly promoted the apoptosis of CMs. In order to investigate the underlying mechanism, RNA‐sequencing (RNA‐seq) was performed, and ingenuity pathway analysis (IPA) was used to analyze the RNA‐seq results. The RNA‐seq data revealed that a total of 2,291 genes were upregulated or downregulated in NR_045363 knockdown CMs, and the IPA analysis indicated that tumor protein 53 (p53) was the upstream regulator. In vivo, the NR_045363 overexpression through the AAV9 system improved the heart function after MI in 7‐day‐old mice and inhibited the CM apoptosis. These data suggest that NR_045363 is involved in CM apoptosis and that NR_045363 overexpression exerts positive effects on cardiac repair by alleviating CM apoptosis through the inhibition of the p53 pathway.

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Tumor suppressive role for kinases phosphorylating p53 in DNA damage‐induced apoptosis

Cited by 124 publications

References 74 publications

Phosphorylation-dependent regulation of the NOTCH1 intracellular domain by dual-specificity tyrosine-regulated kinase 2

Phosphorylation-dependent regulation of the NOTCH1 intracellular domain by dual-specificity tyrosine-regulated kinase 2

Analysis of TP53 gene in uterine myomas: No mutations but P72R polymorphism is associated with myoma development

The long noncoding RNA NR_045363 involves cardiomyocyte apoptosis and cardiac repair via p53 signal pathway

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